The etiology of autoimmune type 1 diabetes is unknown and no effective prevention method has been developed yet. While the common insulin treatment may regulate blood glucose levels to some extent, but long-term use cannot control the occurrence of complications of diabetic effectively, and some patients may encounter hypoglycemia shock. How to prevent autoimmune attack on islet β cells and develop effective β cell transplantation treatment has become a crucial issue in diabetes research.
At present, rodents are the most commonly used animal models in diabetes study. Since rodents are far away from human beings on the evolutionary relationships, the experimental data obtained by studying them have little clinical significance. Rhesus monkey has the similar anatomical characteristics, physiological functions of various systems, and response to diseases and drugs to human beings and is a sensitive animal for evaluating preclinical efficacy and safety of immunological-related treatments, stem cell transplantation, and heterotransplantation. The use of rhesus diabetes model for evaluation of new diabetes drugs and study of immune rejection mechanism and transplantation tolerance induction of islet stem cells and islet heterotransplantation is an internationally recognized pre-clinical experimental system, which has important guiding significance to future clinical application of these treatment programs. Therefore it is an urgent demand to establish a non-human primate model of diabetes for the islet (stem) cell transplantation research and preclinical drug evaluation.
Now the commonly used diabetes animal models include experimental diabetes animal model and spontaneous diabetes animal model. The spontaneous model has higher application value, but cannot be widely used due to low incidence, expensive cost, strict feeding and breeding conditions. Experimental model is used more widely and commonly used induction methods include pancreatic resection, chemical drug induction, virus infection, antagonizes insulin factor, food induction and fattening. Chemical drug induction method is highly thought of by many researchers due to its simple operation and high feasibility; however, in these methods streptozotocin has relatively small toxicity to body tissues and allowing animals have high survival rate, and is more widely used for preparing animal model of diabetes at home and abroad.
Streptozocin (STZ) is an induced reagent that is commonly used for preparing models of diabetes, which has selective destruction of pancreatic β cells of certain animal species, making many animals develop diabetes and the most commonly used of streptozocin is in rat model. Common induction method is as follows: the rats are fasted for 12 h and intraperitoneally injected with 60 mg/kg body weight of STZ once a day for two consecutive days to prepare a rat model of type 1 diabetes successfully. And such model has the characteristics of high blood glucose, mitigated weight, polydipsia, polyphagia and polyuria, which are consistent with the clinical type 1 diabetes; however, in this experiment, when the model is injected intraperitoneally with STZ only once and fed with high calorie feed for 12 weeks, then the model prepared is an animal model of type 2 diabetes, and the model prepared by such method has the characteristics of overweight, reduced glucose tolerance, elevated blood lipids, elevated serum insulin and reduced insulin receptor binding along with insulin resistance, which are similar to the clinical features of patients with type 2 diabetes. The preparation of animal models of type 1 diabetes and type 2 diabetes may be related to the injection dose of STZ: when injected with high dose of STZ (usually 120 mg/kg), due to the directly extensive destruction of pancreatic β cells, type 1 diabetes model is prepared; when injected with low dose of STZ, partial function of pancreatic β cells is destroyed, causing peripheral tissue not to be sensitive to insulin. Meanwhile high calorie feed is given. The combination of two conditions induce an animal model, the pathological and physiological changes of which are close to that of human type 2 diabetes. Therefore, the dose of STZ directly determines the type of the diabetic animal model prepared.
Establishment of rhesus monkey model of diabetes with STZ has been reported in some references, such as: KUANG De-xuan, et al. (Effect of Different Dosage of Streptozotocin on Some Physiological Data in Rhesus Monkey, Acta Lab Anim Sci Sin, March, 2003, Vol. 11, No. 1) studied the physiological data of food and water intake, urination, body weight, plasma glucose and glycosuria with streptozotocin (STZ) in rhesus monkeys, which was essential to establish animal model for diabetes. Methods: Seven rhesus monkeys were injected intravenously with different doses of STZ. The administration dose and method of STZ are as follows: low dose of 30 mg/kg, with an interval of 15 days, repeatedly injected for once to twice; mild dose of 45 mg/kg, injected with STZ once; high dose of 60 mg/kg, injected once. Experimental results: The seven monkeys showed the same clinical features as those of diabetes patients at a different time and extent, such as polyphagia, polydipsia, polyuria, hyperglycosuria, body weight loss. The clinical characteristics were lightened and controlled by using insulin. Especially the clinical symptoms of mild-dose and high-dose of STZ were more obvious than those of low-dose in monkeys. The body weight of low-dose monkeys rose in a short time, then dropped rapidly. Plasma glucose and glycosuria of monkeys were increased with STZ injected, especially mild-dose and high-dose monkeys varied obviously. Thus, the acute animal model similar to human diabetes was induced by mild-dose and high-dose of STZ (45-60 mg/kg). The course of animal model of diabetes may be extended by using insulin treatment or low-dose of STZ, which is suitable for studying complications of diabetes. Biochemical changes in rhesus monkey during the first days after streptozotocin administration are indicative of selective beta cell destruction, Takimoto G, Jones C, Lands W, Bauman A, Jeffrey J, Jonasson O., Metabolism. 1988 April; 37(4): 364-70. 22 rhesus monkeys were selected and injected intravenously with STZ (45 to 55 mg/kg). Almost half of the monkeys developed insulin-dependent diabetes within five days after injection. Four of the remaining monkeys did not become insulin dependent for at least 6 months after STZ administration, during which time they were considered non-insulin-dependent, and the remaining eight monkeys never required exogenous insulin.
Autoimmune diabetes may be divided into diabetes in children and adolescents and latent autoimmune diabetes in adults (LADA), which are subtypes of type 1 diabetes. They have the characteristics as follows: 1) Diabetes in children occurs at age under 15 years old, while LDAD may occur at any age over 15 years old. They are not insulin-dependent within half of a year after outset and have no ketosis; 2) Most patients are non-obese at the outset of diabetes; 3) Islet B cell antibodies in vivo (such as ICA, GAD and insulin autoantibodies) are always positive; 4) They have predisposing genes of type 1 diabetes (such as HLA-DR3, HLA-DR4, BW54 and DQ-131-57-Non-Asp); 5) They are often accompanied by specific antibody positive of organs such as thyroid and gastric parietal cells. Once diagnosed as LDAD, insulin treatment should be applied in early stage to protect the relict β cells. The information about patients in Europe and the United States shows that LADA accounts for about 10%-15% of type 2 diabetes, and the ratio was up to 50% in non-obese patients with type 2 diabetes. It is reported that the positive rate of GAD-Ab in patients with type 2 diabetes is 14.2%. The cause of this type is insulin deficiency caused by autoimmune destruction of islet β cells. Markers of the autoimmune process include lymphocytic infiltration of pancreatic islets and pancreatic islet cells autoantibodies, islet cell antigen autoantibodies, and detection of insulin autoantibodies.
While the reference has reported that rhesus monkey animal model of insulin-dependent diabetes could be induced by mild-dose and high-dose of STZ (45-60 mg/kg), primate animal models of autoimmune type 1 diabetes prepared by low dose of STZ (less than 30 mg/kg) has not been reported yet.